Filling the evidence gaps within cardiovascular disease (CVD) has been identified as a priority by the Agency for Healthcare Policy and Research (AHRQ), and, as emphasized by a report from the AHRQ Effective Healthcare Program, important questions remain regarding the effectiveness of high-dose statins for the secondary prevention of CVD in complex patient subgroups. Randomized controlled trials have shown that aggressively lowering low density lipoprotein cholesterol (LDL-C) with high-dose statins can result in an additional 16% reduction in CVD events compared to moderate-dose statins. Subgroup analyses of trial data also suggest that the benefits of high-dose statins may be even greater for complex CVD patients. Current US guidelines recommend at least a 50% reduction in LDL-C as desirable for cardiovascular prevention and that a more aggressive LDL-C goal <70 mg/dl be considered for very high risk patients. Although most patients require a high-dose statin to achieve guideline recommendations, only <25% of high risk patients in practice receive one. Wide prescribing variation, use of lower potency generic statins due to cost concerns, concerns about safety, and the existence of a "treatment risk paradox" in which complex patients are less likely treated, suggest that providers remain uncertain as to the benefits and harms of treatments for many complex CVD patients. Providers may believe that the benefits and harms of high-dose statins are heterogeneous across patients and in practice they are sorting patients based on these beliefs. Are providers missing benefit opportunities by not expanding high-dose statin prescribing rates among complex CVD patients or do current high-dose statin prescribing rates represent a correct balancing by providers of the benefits and harms across patients? As stated many years ago by John Wennberg, the real question is "Which rate is right?" This proposal is responding to the analytical epidemiological studies component of RFA-HS- 10-009. In this study we will conduct a retrospective cohort study assessing the comparative effectiveness of high-dose statins for complex patients post acute myocardial infarction (AMI) since those with AMI have a clear indication for high-dose statin therapy. We will take advantage of the large number of Medicare patients with AMI that have Medicare "Part D" prescription drug coverage in the Centers for Medicare &Medicaid Services (CMS) Chronic Condition Data Warehouse (CCW) to analyze the effectiveness of high-dose statins within subsets of complex AMI patients. Complex AMI patients will be defined by the presence of diabetes, congestive heart failure (CHF), and chronic kidney disease (CKD), conditions that place AMI patients at very high cardiovascular risk.3, 39, 40 Our analytical framework includes using both risk adjustment (RA) estimators (including propensity score methods) and moment-based instrumental variable (IV) estimators and interprets their estimates in terms of the distinct treatment effect concept produced by each estimator. Because it appears that high- dose statin utilization rates have lagged behind guideline recommendations, we hypothesize that (1) the patients that received high-dose statins had cardiovascular event-free survival gains sufficient to justify side-effect risks and healthcare costs;and (2) that higher high-dose statin treatment rates would increase cardiovascular event-free survival rates enough to justify increased side-effect rates and healthcare costs. The aims of this research are consistent with both the clinical and methodological goals of the AHRQ Comparative Effectiveness Portfolio. Our methodological approach is innovative because we will (1) assess the comparative effectiveness of high-dose statins using both RA and IV approaches in light of the correct interpretations of estimates from these methods;and (2) exploit the large number of AMI Medicare patients from the CCW to estimate the comparative effectiveness of high-dose statins complex subsets of AMI patients The research team has the unique combination of clinical, methodological, and empirical expertise that is necessary to perform the proposed research. PUBLIC HEALTH RELEVANCE: Current US guidelines suggest that high risk complex patients with CVD receive high-dose statins, yet providers are not prescribing high-dose statins to most complex elderly CVD patients. Because the benefits and harms of high-dose statins appear heterogeneous across patients, insufficient evidence exists to assess whether current high-dose statin treatment rates represent over- or under-utilization for complex CVD patients. The results of this study will help clinicians, guideline-makers, and policy-makers understand the benefits, risks, and costs associated with high-dose statin treatments for complex CVD patients.